Lysosomes as mediators of drug resistance in cancer
作者:Benny Zhitomirsky, Yehuda G. Assaraf
摘要:Drug resistance remains a leading cause of chemotherapeutic treatment failure and cancer-related
mortality. While some mechanisms of anticancer drug resistance have been well characterized, mul-
tiple mechanisms remain elusive. In this respect, passive ion trapping-based lysosomal sequestration
of multiple hydrophobic weak-base chemotherapeutic agents was found to reduce the accessibility
of these drugs to their target sites, resulting in a markedly reduced cytotoxic effect and drug resis-
tance. Recently we have demonstrated that lysosomal sequestration of hydrophobic weak base drugs
triggers TFEB-mediated lysosomal biogenesis resulting in an enlarged lysosomal compartment, capable
of enhanced drug sequestration. This study further showed that cancer cells with an increased num-
ber of drug-accumulating lysosomes are more resistant to lysosome-sequestered drugs, suggesting a
model of drug-induced lysosome-mediated chemoresistance. In addition to passive drug sequestration
of hydrophobic weak base chemotherapeutics, other mechanisms of lysosome-mediated drug resistance
have also been reported; these include active lysosomal drug sequestration mediated by ATP-driven
transporters from the ABC superfamily, and a role for lysosomal copper transporters in cancer resistance
to platinum-based chemotherapeutics. Furthermore, lysosomal exocytosis was suggested as a mech-
anism to facilitate the clearance of chemotherapeutics which highly accumulated in lysosomes, thus
providing an additional line of resistance, supplementing the organelle entrapment of chemotherapeu-
tics away from their target sites. Along with these mechanisms of lysosome-mediated drug resistance,
several approaches were recently developed for the overcoming of drug resistance or exploiting lysoso-
mal drug sequestration, including lysosomal photodestruction and drug-induced lysosomal membrane
permeabilization. In this review we explore the current literature addressing the role of lysosomes in
mediating cancer drug resistance as well as novel modalities to overcome this chemoresistance.
关键词:cancer ,Chemotherapeutics ,Drug sequestration ,Drug transport, Lysosomes, Multidrug resistance
论文方向:[{"id":918,"name":"药物学"}]
发表期刊:
数字识别码:DOI: 10.1016/j.drup.2015.11.004
是否作者本人: 否
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